Physiol Rev

84: 385– 410, 2004; 10.1152/physrev.00026.2003.

Pleural Mechanics and Fluid Exchange

STEPHEN J. LAI-FOOK

Center for Biomedical Engineering, University of Kentucky, Lexington, Kentucky

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I. Introduction 385
A. Historical perspective: hydrostatic equilibrium versus viscous flow 386
II. Pleural Pressure 386
A. Regional lung volume and pleural pressure 386
B. The question of pleural contact 388
C. Measurements of pleural pressure 389
D. Pleural pressure at lobar margins and zone of apposition of rib cage to the diaphragm 390
III. Pleural Liquid Thickness and Lubrication 391
A. Ventilation, microvascular filtration, and energy dissipation 391
B. Pleural liquid volume and cell composition 393
C. Microvilli: spatial distribution 393
D. Hyaluronan as a pleural lubricant 393
IV. Circulation of Pleural Liquid 394
A. Gravity-dependent flows: absence of hydrostatic equilibrium 394
B. Upward flow along lobar margins 395
C. Transverse flows: the ventilatory pump 396
D. Fluid volume homeostasis 396
V. Microvascular Exchange 396
A. Pleural anatomy and blood supply 396
B. Transport equations: Starling and solute flux equations 396
C. Hydraulic conductivity, reflection coefficient, and diffusive permeability 397
D. Pleural filtration pressure and filtration and absorption rates 400
E. Regional absorption, role of lymphatics, and regional filtration 403
VI. Pleural Liquid Protein Concentration 404
A. Effect of body size, vascular pressure, ventilation, and regional differences 404
B. Active protein and solute-coupled liquid transport 405
C. Clearance by lymphatic stomata versus mesothelial absorption 406
VII. Concluding Remarks 406

Lai-Fook, Stephen J. Pleural Mechanics and Fluid Exchange. Physiol Rev 84: 385– 410, 2004; 10.1152/phys-
rev.00026.2003.—The pleural space separating the lung and chest wall of mammals contains a small amount of liquid
that lubricates the pleural surfaces during breathing. Recent studies have pointed to a conceptual understanding of
the pleural space that is different from the one advocated some 30 years ago in this journal (Agostoni E. Physiol Rev
52: 57–128, 1972). The fundamental concept is that pleural surface pressure, the result of the opposing recoils of the
lung and chest wall, is the major determinant of the pressure in the pleural liquid. Pleural liquid is not in hydrostatic
equilibrium because the vertical gradient in pleural liquid pressure, determined by the vertical gradient in pleural
surface pressure, does not equal the hydrostatic gradient. As a result, a viscous flow of pleural liquid occurs in the
pleural space. Ventilatory and cardiogenic motions serve to redistribute pleural liquid and minimize contact between
the pleural surfaces. Pleural liquid is a microvascular filtrate from parietal pleural capillaries in the chest wall.
Homeostasis in pleural liquid volume is achieved by an adjustment of the pleural liquid thickness to the filtration rate
that is matched by an outflow via lymphatic stomata.

I. INTRODUCTION mental concepts of the mechanics of the pleural space has

undergone a continual evolution. The previous review
Since the last review that appeared in this journal invoked hydrostatic equilibrium of pleural liquid as the
some 30 years ago (1), the understanding of the funda- fundamental principle. In the current review, surface

www.prv.org 0031-9333/04 $15.00 Copyright © 2004 the American Physiological Society 385
386 STEPHEN J. LAI-FOOK
forces due to the opposing elastic recoils of lung and
chest wall are the primary determinants of the pressure in
the intervening pleural liquid. The pleural surface pres-
sure, defined as the force per unit pleural surface area, is
equal to the pressure in the pleural liquid. The difference
between the vertical gradient in pleural pressure and the
hydrostatic value (1 cmH2O/cm height) drives a viscous
flow within the pleural space. A function of the liquid in
the pleural space is to lubricate the pleural surfaces. The
uniform thickness of the lubricating layer is maintained
by recirculation of pleural liquid driven by gravity and
ventilatory and cardiogenic motions. Pleural liquid is a
microvascular filtrate that is cleared by pleural lymphat-
ics, a process similar to that in the interstitium of all body
organs.
The review is divided into the following sequence. A
brief summary of regional volume and pleural pressure is
presented, followed by a description of the different types
of pleural pressure measurements. Then pleural liquid
thickness is described within the context of pleural lubri-
cation. Circulation of pleural liquid within the pleural
space is treated as part of viscous flow theory. The next
section describes the formation of pleural liquid as a
microvascular filtrate and its absorption via lymphatic
stomata. Finally, pleural liquid protein and the factors that
determine its concentration and absorption are discussed.
A. Historical Perspective: Hydrostatic Equilibrium
Versus Viscous Flow
The transmission of forces between the chest wall
and the lung across the pleural space has been explained
in two different ways. In the first, Setnikar et al. (180) and
Agostoni et al. (14) proposed that pleural liquid, like the
capillary blood, was in hydrostatic equilibrium with a
vertical pressure gradient equal to 1 cmH2O/cm height.
They proposed that hydrostatic equilibrium was achieved
by absorption of pleural liquid into the blood until a
balance of hydrostatic and osmotic forces between pleu-
ral liquid and the blood occurred. The absorptive pressure
was calculated to be ⫺11 cmH2O, lower than the surface
pressure required to maintain the lung at its end-expira-
tory volume. The difference between pleural liquid and
surface pressures was attributed to points of contact
between the two pleural surfaces. This concept of the
mechanics of the pleural space has been the focus of
several reviews by Agostoni and co-workers (1, 2, 9, 18).
The second concept (97, 98, 103) is the one that I
emphasize in this review. The surface pressure acting to
expand the lung, equal and opposite to the pressure ex-
panding the chest wall, is transmitted hydraulically across
the thin pleural liquid space with the surface pressure
equal to the pleural liquid pressure. Thus pleural surface
pressure is the major determinant of the pleural liquid
Physiol Rev • VOL
pressure. The difference between the vertical gradient in
pleural surface pressure and the hydrostatic value drives
a viscous flow of pleural liquid downward in the pleural
space. This conception of the mechanics of the pleural
space requires a continuous pleural liquid space with no
pleural contact.
II. PLEURAL PRESSURE
A. Regional Lung Volume and Pleural Pressure
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There is a consensus among investigators that re-
gional lung volume within the intact thorax varies with
body position relative to gravity. Early bronchospirome-
try studies in humans in the lateral decubitus posture
demonstrated that the dependent lung has a smaller end-
expiratory volume, a larger tidal volume, and larger re-
gional ventilation than the nondependent lung (111). Stud-
ies by Milic-Emili and co-workers (90, 123) using external
scintillation counting of inhaled radioactive xenon in hu-
mans confirmed that vertical gradients in regional lung
volume and ventilation are also present in the upright and
supine positions. Furthermore, in upright humans, the
vertical gradient in transpulmonary pressure calculated
from the vertical gradient in regional lung volume and the
lung pressure-volume curve was found to be consistent
with the vertical gradient of pleural pressure estimated by
esophageal balloons (123). Differences in ventilation be-
tween the dependent and nondependent lung have also
been demonstrated in recumbent humans during mechan-
ical and spontaneous ventilation (169), during anesthesia
and paralysis (171), and with diaphragmatic contraction
(174). The radioactive xenon technique, applied effec-
tively in humans, is not suitable for use in smaller animals
because of its limited spatial resolution. A vertical gradi-
ent in regional alveolar size was measured in dogs frozen
in the head-up (74) and supine (85) postures. Measure-
ments of pleural surface pressure in experimental animals
using a counter-pressure technique produced vertical gra-
dients in transpulmonary pressure that were consistent
with vertical gradients in regional lung volume (8, 12,
61– 63). Comprehensive reviews of these studies have
been written by Agostoni (1, 2).
Measurements of pleural pressure using a variety of
techniques (see sect. IIC) in experimental animals have
demonstrated vertical gradients in pleural pressure in the
head-up (35, 57, 83, 87, 89, 99, 189, 191, 214), head-down
(57), supine (1, 2, 98, 159, 160, 175, 214 –216), prone (175),
and lateral decubitus (1, 2) positions. With few excep-
tions, the results of these studies were generally consis-
tent with regional pleural surface pressure inferred from
studies of the vertical distribution in regional volume.
However, the measured vertical gradients in pleural pres-
sure were often greater than the vertical gradient for a
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 MECHANICS OF THE PLEURAL SPACE
fluid with the density of the lung (103). A structural (finite
element) analysis by West and Matthew (210) of the ef-
fects of gravity on the lung modeled as a compliant solid
showed a vertical gradient in transpulmonary pressure of
0.2 cmH2O/cm height, close to the value for a fluid having
the density of the lung. Thus vertical gradients in transpul-
monary pressure greater than the one predicted from the
lung density implied the contribution of forces in addition
to lung weight. This was supported by studies in experi-
mental animals that showed a reduced vertical gradient in
pleural surface pressure on removal of the abdominal
contents (1, 2).
The development of sophisticated imaging tech-
niques with high spatial resolution provided evidence of
regional differences in lung volume that were not de-
tected by the previous techniques. Roentgenographic im-
aging of intraparenchymal lung markers in supine dogs
showed vertical and cranial-caudal gradients of regional
lung volume (88). Computerized tomographic imaging of
regional lung density in the dog (82, 84), sloth (84), and
human (32) demonstrated vertical gradients of regional
lung volume in the supine position. These observations
were generally consistent with previous measurements of
pleural surface pressure. The imaging techniques also
showed that lung volume was more uniform in the prone
than in the supine position (Fig. 1), a behavior that was
not detected in previous studies. The prone position was
also found to have a more uniform blood flow distribution
(25, 66, 211).
Following the structural studies of the effects of
gravity on the lung (210), more complex models were
developed to show the effects of the weight of the heart
and abdomen on the vertical gradient in transpulmonary
pressure in different body positions. In addition to the
weight of the abdomen (1, 2), the effects of gravity on the
heart have been shown to contribute to the vertical gra-
dient in transpulmonary pressure, more in the supine and
Physiol Rev • VOL
387
upright positions than in the prone and head-down posi-
tions. In the supine position, compression of the dorsal
lung regions by the weight of the heart produced a rela-
tively large vertical gradient in transpulmonary pressure
(112). This effect was absent in the prone position, where
the weight of the heart was supported by the sternum and
had little effect on regional lung volume (24). A structural
analysis that included the abdomen with a compliant
diaphragm, in addition to the lung and heart, showed a
caudal extension of the ventral region of the lung in the
supine position that was absent in the prone position.
This cranial-caudal extension of the ventral regions to-
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gether with a cranial-caudal shortening of the dorsal re-
gions due to the weight of the heart and abdomen pro-
duced a change in shape of the diaphragm in the supine
position from that present in the prone position (see Fig.
1, insets), with only a relatively small effect on end-
expiratory lung volume (73, 112).
In the upright position, compression of the caudal
lung regions by the weight of the heart contributes to the
vertical gradient in transpulmonary pressure. This effect
of the weight of the heart was predicted using a structural
analysis of the lung and heart (36). This prediction was
verified experimentally by esophageal pressure measure-
ments in the head-up dog in which the weight of the heart
was increased by filling it with mercury (89). In the up-
right position, inclusion of the abdomen with a compliant
diaphragm in the structural analysis showed a cranial-
caudal lung extension by abdominal weight that increased
the vertical gradient in transpulmonary pressure and the
end-expiratory lung volume (73). The structural analysis
also showed a smaller vertical gradient in the head-down
than upright position. In the head-down position, the
weight of the heart and abdomen compressed the entire
lung and reduced the end-expiratory volume to near the
residual volume, which resulted in a relatively small ver-
tical gradient in transpulmonary pressure. This explana-
FIG. 1. Variation of lung air content
with height measured in the anesthetized
dog in the supine and prone position at
functional residual capacity (FRC). Note
the large variation of lung air content
with height in the supine position com-
pared with the constant value in the
prone position. Insets show the change
in shape in diaphragm surface from su-
pine to prone positions. [From Hoffman
(82).]
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388 STEPHEN J. LAI-FOOK
tion for the relatively small vertical gradient in the head-
down position contrasts to that for the prone position,
where support of the weight of the heart and abdomen by
the sternum and spine, respectively, results in little
change in regional lung volume.
Measurements of pleural liquid pressure using rib
capsules implanted in dogs showed a greater vertical
gradient in the supine than prone position (99, 214) and
matched the behavior in pleural surface pressure inferred
from measurements of regional lung volume (88) and
density (82, 84). A similar behavior in pleural liquid pres-
sure was measured in the pony (159) and rabbit (215,
216). However, these results in rabbits were supported by
estimates of pleural surface pressure inferred from alve-
olar size (215, 216) but not by measurements of regional
lung density (158, 160). Rib capsule measurements in the
dog also showed a greater vertical gradient in pleural
liquid pressure in the head-up than in the head-down
position (99) that was similar to the behavior in pleural
surface pressure predicted from the structural analysis
(73). The noted exception notwithstanding, the agree-
ment among the results of regional lung volume and den-
sity, structural analyses and rib capsule measurements of
pleural liquid pressure supports the concept that pleural
surface pressure is equal to pleural liquid pressure. Fur-
ther support for this concept was provided by the rib
capsule studies in which the pleural liquid pressure inter-
polated to midlung height was equal to the mean lung
static recoil measured by the airway pressure after oc-
cluding the airway and opening the chest.
An unresolved issue is the effect of lung inflation on
the vertical gradient in transpulmonary pressure. Some
studies showed a reduced or constant vertical gradient in
transpulmonary pressure (12, 87) with lung inflation,
while other studies showed an increased gradient with
lung inflation (36, 89, 216). In evaluating the effects of
lung inflation, it is important to distinguish between the
vertical gradient in regional volume and the vertical gra-
dient in transpulmonary pressure. The vertical gradient in
regional lung volume disappears with lung inflation because
lung compliance becomes progressively smaller at higher
transpulmonary pressures even in the presence of mea-
surable vertical gradients in transpulmonary pressure.
More detailed reviews of regional lung volume and
ventilation distribution have been published (122, 170).
For the present purpose, the important conclusion is that
regional lung volume distribution is determined by the
interaction among the forces in the lung, thoracic and
abdominal cavities attenuated by the effects of gravity
that change with body position (170). In the supine and
upright positions, there is a relatively large vertical gradi-
ent in regional lung volume that is produced by the com-
bined effects of gravity acting on the lung, heart, and
abdomen. In the prone position, the regional lung volume
along the vertical axis is more uniform because the effects
Physiol Rev • VOL
of gravity are relatively small. In the head-down position,
vertical differences in regional volume are virtually ab-
sent in the highly compressed lung.
Pleural pressure couples the lung to the rib cage and
diaphragm via a thin liquid film that lubricates the pleural
surfaces during breathing. Because the vertical pleural
pressure gradient is always less than the hydrostatic
value, part of the gravity force drives a small viscous flow
of liquid downward in the pleural space. This small flow
does not affect the distribution of pleural surface pressure
that is determined by the force balance between the lung
and adjacent structures.
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B. The Question of Pleural Contact
The controversy regarding force transmission across
the pleural space was fueled by large differences between
the vertical gradient of transpulmonary pressure and the
vertical gradient of pleural liquid pressure measured by
intrapleural catheters that was near the hydrostatic value.
The first explanation of these differences was to postulate
the existence of points of contact between the two pleural
surfaces to make up the difference between pleural sur-
face pressure and pleural liquid pressure (1, 2). In the
absence of any experimental evidence of points of contact
(7, 11, 13), contact through cells present in pleural liquid
and microvilli was proposed (1, 2). Although some con-
tact most likely occurs in the pleural space, the relevant
question is whether its magnitude is sufficient to affect
substantially the equality between liquid and surface pres-
sures.
Perhaps the major objection to contact forces as an
explanation for the differences between pleural surface
pressure and pleural liquid pressure measured by in-
trapleural catheters is the prohibitively large pressures
that have to be attributed to pleural contact. In small
mammals of small lung height, such as the rat, contact
pressures would be relatively small, of the same order of
magnitude as pleural surface pressure (approximately ⫺2
cmH2O). However, in large mammals, such as humans,
contact pressures would have to be much larger than
pleural surface pressure. For example, consider an up-
right human with a vertical surface pressure gradient of
0.3 cmH2O/cm (122) and a hydrostatic gradient in pleural
liquid pressure (1 cmH2O/cm). With the pressures at the
lung base of 0 cmH2O (6), the difference in pleural surface
and liquid pressures at the lung apex located 30 cm above
the lung base would be 21 cmH2O, more than double the
pleural surface pressure of 9 cmH2O. It is unlikely that
cells present in pleural liquid (127, 177) and microvilli
(198 –200) are numerous enough to account for this dif-
ference, since they occupy ⬍1 and 3% of the surface area,
respectively (see sect. III). Moreover, the required contact
pressure would have to be even greater in animals larger
than humans.
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 MECHANICS OF THE PLEURAL SPACE
The concept of a hydrostatic gradient of pleural liq-
uid pressure was accompanied by the need to postulate a
net absorptive pressure for the pleural space to satisfy the
Starling force balance for zero microvascular filtration
required for hydrostatic equilibrium. As with contact
points, there is little evidence for a net absorptive pres-
sure in the pleural space (see sect. V). Accordingly, an
alternative explanation based on viscous flow theory for
the difference between the vertical gradient in pleural
surface pressure and the hydrostatic value seems more
plausible, particularly in view of evidence of flow redis-
tribution occurring within the pleural space. Before the
viscous flow theory is discussed as it applies to the me-
chanics of the pleural space, it is helpful to review various
techniques for measuring pleural pressure because differ-
ences between pleural surface and liquid pressures might
be attributed to the distortions introduced by the measur-
ing devices themselves.
C. Measurements of Pleural Pressure
A definitive direct measure of pleural pressure has
remained elusive because the pleural space is very thin, of
the order of 5–35 ␮m (7, 11, 13, 27, 100, 101, 204, 202). This
is demonstrated in Table 1, a summary of the vertical
pleural pressure gradients measured in the head-up dog at
end-expiratory lung volume by a variety of methods. Pleu-
ral liquid pressure was measured by the first three methods,
and pleural surface pressure was measured by the remain-
ing four methods. The vertical gradients range from 0.2 to
0.9 cmH2O/cm height. The smaller values (0.2– 0.3 cmH2O/
cm) were obtained with flat pleural balloons (87, 96, 118,
168), the larger values (0.7– 0.9 cmH2O/cm) with liquid-
filled intrapleural catheters and needles (35, 57, 189).
Intermediate values (0.4 – 0.5 cmH2O/cm) for the pleural
pressure gradient were measured by other methods:
esophageal balloons (89, 191), counter pressure devices
(1, 2), alveolar size measurements (74), and rib capsules
(99, 214). The different methods will be discussed in turn
with regard to their strengths and deficiencies.
The esophageal balloon is the only method that is
TABLE 1. Vertical gradient in pleural pressure measured
in head-up dogs
Method Gradient, cmH2O/cm Reference Nos.
Pleural needle 0.93 189
Pleural catheter 0.72 35, 57
Rib capsules 0.53 99, 214
Alveolar size 0.50 74
Esophageal balloon 0.42 89, 191
Counter-pressure device 0.40 1, 2
Pleural balloon 0.20–0.30 87, 96, 118, 168
[Modified from Lai-Fook and Rodarte (103).]
Physiol Rev • VOL
389
suitable for measuring pleural pressure in humans (193).
Indeed, it has been used extensively for measuring pul-
monary airway resistance in clinical medicine and in ex-
perimental animals. Because the esophagus is oriented in
a cranial-caudal direction in the mediastinal space be-
tween the lungs, the vertical gradient in pleural pressure
can be measured by this method only in the upright and
head-down body positions (89, 191). The limitation of this
method is that the pressure measured is often attenuated
by the stiffness of the esophagus due to smooth muscle
tone and by the weight of the surrounding mediastinal
structures. As a result, the pressure measured is a func-
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tion of the balloon’s location within the mediastinal space
and of body position and often produces unreliable values
for the lung static recoil (37).
Intrapleural liquid-filled catheters, rigid cannulas,
and needles are relatively easy to implement and have
been extensively used to measure pleural liquid pressure
in experimental animals (1–3, 9, 7, 13, 20, 22, 23, 35, 57,
128, 129, 131, 139, 140, 175, 176). There are two reasons
why intrapleural catheters produce vertical gradients in
pressure near to the hydrostatic value (103). First, the
liquid layer adjacent to a 1-mm-diameter intrapleural cath-
eter is ⬃50-fold thicker than the normal pleural space and
forms a static liquid column along the catheter. A similar
effect occurs at the relatively wide spaces adjacent to
lobar margins (91, 98; Fig. 5). In practice, vertical gradi-
ents measured by intrapleural catheters were often less
than hydrostatic (35, 57, 139, 175, 176), although some
investigators have consistently measured a hydrostatic
gradient with this technique (1, 2, 7, 13). Second, an
abnormally thick pleural space also would exist distal to
the tip of the catheter. Thus a catheter situated near a
lobar margin would be determined partly by the pressure
at the lobar margin, where a hydrostatic gradient exists
(Fig. 2). Intrapleural wick catheters have been used in an
attempt to reduce the distortion of the pleural space, but
like intrapleural catheters, they also spread apart the
pleural space and often produced results similar to those
measured by intrapleural catheters (83).
A number of techniques have been developed to cir-
cumvent the problems associated with intrapleural cath-
eters. They each have advantages and disadvantages.
Flat air-filled pleural balloons (87, 117, 118) have
been used to measure the average recoil of the lung region
adjacent to the surface of the balloons. The placement of
a flat balloon into the pleural space causes an indentation
of the lung surface that reduces the recoil of the lung
adjacent to the balloon and the vertical gradient in pleural
pressure (78, 103, 214). Moreover, the chest must be
opened to install pleural balloons, and any residual air in
the pleural space that is not removed on closing the chest
compresses nondependent lung regions. For the above
reasons, the vertical gradients in pleural pressure mea-
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390 STEPHEN J. LAI-FOOK
FIG. 2. Pleural liquid pressure measured in the prone dog at a lobar
margin and costal surface in the nondependent thorax, and mean lung
static recoil (Pst). Note that pressure at the lobar margin fell along the
line of identity that represented the hydrostatic gradient, while pressure
at the costal surface was less negative and equal to Pst. [Modified from
Lai-Fook (97).]
sured by flat pleural balloons are relatively small (0.2– 0.3
cmH2O/cm).
In the counter-pressure method for measuring pleu-
ral surface pressure, a negative pressure is applied to a
parietal pleural window located in the intercostal space
until the lung surface becomes flat (1, 2, 8, 12). This
method assumes that the undisturbed lung surface is
usually flat, whereas the intercostal lung surface is nor-
mally depressed inwards due to the smaller intercostal
muscle recoil compared with the ribs (86). Thus the mag-
nitude of the counter pressure taken as the pleural sur-
face pressure would differ from that required to produce
a normally curved pleural surface.
Pleural pressure can be estimated by comparing re-
gional alveolar volume measured in vivo to the pressure-
volume behavior measured in the isolated lung (61, 215,
216). The measurement of alveolar size through parietal
pleural windows also requires the removal of intercostal
muscle, and therefore, the lung region beneath the win-
dow has reduced elastic recoil. In spite of these limita-
tions, these techniques for measuring pleural pressure
produced results that were in general consistent with
measurements of lung volume distribution.
Two methods, the micropuncture (98, 129) and rib
capsule techniques (99, 159, 160, 214, 216), have been
used to measure pleural liquid pressure with minimal
distortion of the pleural space. In the micropuncture tech-
Physiol Rev • VOL
nique, pleural liquid pressure is measured in conjunction
with a servo-nulling device through a micropipette tip
(2–5 ␮m diameter) that is smaller than the pleural space
thickness. Like the techniques that measure a counter
pressure and alveolar size, the micropuncture technique
requires the removal of intercostal muscle to puncture the
parietal pleura, which would reduce the local lung elastic
recoil. Because the micropipette tip is difficult to visualize
in tissue, its exact location cannot be determined with
certainty. Furthermore, pleural pressure can be measured
only during apnea because the glass micropipette is easily
broken.
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In the rib capsule technique, a capsule is implanted in
a rib and a small hole is made in the parietal pleura to
allow pressure communication between the liquid in the
capsule and the pleural liquid. The rib capsule is similar in
concept to the intercostal capsule (10), but the rib capsule
technique avoids the reduced recoil caused by removal of
intercostal muscle. A limitation of the rib capsule tech-
nique is that measurements are confined to the pleural
space under ribs, where pleural pressure might be slightly
less than that beneath intercostal muscle because of the
stiffer rib (86).
D. Pleural Pressure at Lobar Margins and Zone
of Apposition of Rib Cage to the Diaphragm
1. Lobar margins
Although a hydrostatic gradient in pleural pressure is
not generally attained in the pleural space, there are
spaces such as at lobar margins where a hydrostatic
gradient is established (91, 98). A cross-section of a lobar
margin in the rabbit measured using the light micro-
scopic-focusing technique (101) is shown in Figure 5 (see
sect. IV). Note that the pleural liquid thickness adjacent to
the margin of the middle lobe is much greater than that on
the flat costal surface. The reason for the hydrostatic
gradient, within the context of viscous flow concepts (see
sect. IV) is that at lobar margins the pleural space is wide
enough so that the viscous losses are negligible, similar to
the effect observed in blood capillaries. Also at lobar
margins the vertical gradient in pleural liquid pressure is
matched by the appropriate vertical variations in lung
surface curvature and pleural membrane tension that are
not possible on the relatively flat costal lung surface.
Micropuncture measurements of pleural liquid pressure
in the nondependent region of prone rabbits (98) and
prone dogs (91) showed the pressure at the lobar margin
to be more negative than on the costal surface (Fig. 2).
Similar results were obtained using rib capsules (194).
Under conditions of apnea in nondependent regions,
where pleural liquid pressure at the lobar margin is more
negative than the pressure on the adjacent costal surface
(Fig. 2), pleural liquid flows from the costal surface to the
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 MECHANICS OF THE PLEURAL SPACE
lobar margin regions. The difference between the costal
surface pressure and the lobar margin pressure decreases
with distance down the lung. This should result in an
increased pleural space thickness down the lung, a be-
havior not substantiated by the uniform pleural space
thickness measured (7, 27, 101). However, the costal sur-
face-to-lobar margin flow that occurs during apnea is
offset by a ventilation-induced reverse flow (see sect. IV).
2. Zone of apposition of rib cage to the diaphragm
In the zone of apposition of the diaphragm to the rib
cage, pleural pressure increases during spontaneous in-
spiration (3, 166, 194). This behavior resembles that of
abdominal pressure (1, 2) and is opposite to that of pleu-
ral pressure on the lung surface, which decreases on
inspiration. Thus the vertical gradient in pleural pressure
in the zone of apposition is near the hydrostatic value and
similar to the vertical gradient in abdominal pressure (3,
113).
III. PLEURAL LIQUID THICKNESS
AND LUBRICATION
In terms of lubrication of the pleural surfaces, pleural
liquid thickness is important to the evaluation of pleural
contact and of the magnitude of shear stress induced
during ventilation. Two types of pleural lubrication have
been postulated. One is fluid lubrication based on viscous
shear stresses developed in a fluid layer interposed be-
tween sliding surfaces (46). The second is boundary lu-
brication where the fluid layer thins so that part of the
surfaces comes into contact.
A. Ventilation, Microvascular Filtration,
and Energy Dissipation
For fluid lubrication in its simplest form, the forces
that are generated by the sliding between the lung and
Physiol Rev • VOL
391
chest wall during breathing are given by Newton’s law of
viscosity (46)
␴ ⫽ ␯ V/h (1)
The shear stress (␴) in pleural liquid is related to the
lung-chest wall relative velocity (V), pleural liquid viscos-
ity (␯), and pleural liquid thickness (h). The advantage of
fluid lubrication is that resistance to motion arises from
fluid viscosity, and friction on the pleural surfaces is
virtually absent.
Pleural liquid thickness measured by a variety of
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techniques is extremely thin, varying between 5 and 35
␮m. These techniques included light microscopic imaging
of frozen samples (7, 11, 13), electron microscopy (27),
light microscopic focusing (100, 101), and fluorescent
imaging (204, 202). Generally pleural liquid thickness was
uniform with respect to height in the thorax, except for a
slight gradient in the sheep (27), and at lobar margins (27)
and the lung base where it was much thicker (101). In our
study (101), pleural liquid thickness during apnea in-
creased with animal size, ranging from 7 ␮m in the mouse
to 23 ␮m in the dog. The allometric relationship (182, 183)
between pleural liquid thickness and animal mass (M)
was (101): h ⬀ M0.20 (Fig. 3).
1. Effect of ventilation
The imaging of fluorescent dye injected into the pleu-
ral liquid of rabbits showed that pleural liquid thickness
increased with ventilation (204, 202). In this technique,
the thickness of the pleural space was measured from the
fluorescent light emitted by the pleural liquid through a
parietal pleural window made in the intercostal space.
Pleural liquid thickness measured from the fourth inter-
costal space was minimal (11 ␮m) during apnea and
increased to ⬃35 ␮m with increases in tidal volume (202).
A similar behavior was observed with increases in venti-
FIG. 3. Pleural liquid thickness (h)
versus body mass (M) measured by light
microscopy in five laboratory species
during apnea. Note that thickness in-
creased with body mass during apnea:
h ⬀ M0.20, consistent with pleural liquid
filtration that scales with body mass
(solid line). Dashed line is the allometric
relation (h ⬀ M0.08) predicted for ventila-
tion with the assumption of a constant
pleural liquid shear stress among spe-
cies. Point (open circle) is the value mea-
sured in rabbits during mechanical ven-
tilation. [Modified from Lai-Fook and
Kaplowitz (101).]
84 • APRIL 2004 • www.prv.org
392
lation frequency. This behavior was qualitatively consis-
tent with a ventilatory pump (see sect. IV) that drives
pleural liquid from the lobar margins to the flat costal
surfaces, a behavior opposite to that expected during
apnea (54). In subsequent studies, the thickness of the
pleural space was measured using the fluorescent dye
technique at three pleural windows located along the
cranial-caudal axis (204). These studies showed that pleu-
ral liquid thickness increased along the cranial-caudal
axis from a minimal value of 5 ␮m in the second inter-
costal space to a value of ⬃30 ␮m in the fifth intercostal
space (Fig. 4A). This cranial-caudal gradient in pleural
liquid thickness increased with ventilation, primarily due
to an increased thickness in the caudal regions. The am-
plitude of lung velocity relative to that of the rib cage also
showed a similar gradient that increased with frequency
(Fig. 4B). This behavior is predictable from a uniform lung
expansion caused predominantly by diaphragmatic con-
traction (119). Since the increase in pleural liquid thick-
ness offset the increase in relative velocity (Eq. 1), shear
stress amplitude in pleural liquid was constant with cra-
nial-caudal distance but increased with ventilation fre-
quency (Fig. 4C).
Three factors might contribute to the cranial-caudal
gradient in pleural liquid thickness and constant shear
stress. First, redistribution of pleural liquid associated
with a ventilation-induced flow from lobar margins (see
sect. IV) would be greater for the caudal lobe with a
greater lung-chest wall relative velocity than for the cra-
nial lobe. Second, a cranial-caudal gradient in pleural
liquid thickness might be matched by a cranial-caudal
gradient in filtration (see sect. V). Third, the lung within
the chest wall might act like a shaft in a cylinder under
FIG. 4. Pleural liquid thickness (A), lung-chest wall relative velocity amplitude (B), and pleural liquid shear stress
amplitude (C) versus cranial-caudal distance. Note that both thickness and velocity increased with cranial-caudal
distance. This behavior produced a constant shear stress with cranial-caudal distance. [Modified from Wang and
Lai-Fook (204).]
Physiol Rev • VOL
STEPHEN J. LAI-FOOK
load (46) where the load (Po) caused by lung buoyancy
(76) forces the lung against the chest wall. By fluid lubri-
cation theory (46), the distance of nearest approach of the
lung to the chest wall is proportional to ␯V/Po so that
pleural liquid thickness increases with relative velocity
(V) which increases with cranial-caudal distance.
A limitation of the microscopic focusing and fluores-
cent dye techniques is that a parietal pleural window is
required. Accordingly, pleural liquid thickness measured
through pleural windows might be affected by the re-
duced lung static recoil beneath the window (204). Given
the small size of the window (2 mm diameter), the local
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recoil would depend more on the membrane tension and
less on the intercostal muscle dissected (78). Further-
more, since any reduced recoil was constant, it is unlikely
to account for the measured changes with frequency or
cranial-caudal position.
Under apneic conditions pleural liquid thickness in-
creased with animal size, h ⬀ M0.20 (Fig. 3). This allomet-
ric relationship was explained by a pleural liquid filtration
rate that scaled with body mass (101), with the assump-
tions of a constant net driving pressure gradient and a
downward flow of pleural liquid that represents the filtra-
tion rate (see Eq. 2, sect. IV). A pleural liquid filtration rate
of 0.01– 0.02 ml䡠h⫺1䡠kg⫺1 (see Table 7) has been estimated
in the sheep (212), dog (124, 152), and rabbit (48).
With the assumption that during ventilation shear
stress in pleural liquid is constant among species, the
allometric relationship is (104) h ⬀ M0.08 (Fig. 3). Thus,
during ventilation, the increase in pleural liquid thickness
with body mass would be smaller than that measured
during apnea.
Based on the pleural space thickness of the rabbit
84 • APRIL 2004 • www.prv.org
 MECHANICS OF THE PLEURAL SPACE 393

measured with mechanical ventilation (Fig. 4B), the two TABLE 2. Volume of pleural liquid
allometric curves converge as body mass increases (Fig.
Body Weight, Pleural Liquid Volume, Reference
3). This is because as breathing frequency is reduced with Species kg ml/kg Nos.
body mass (frequency ⬀ M⫺0.25; Refs. 182, 183), condi-
tions of apnea are approached. The intersection of the Rat 0.45 0.6 137
two curves occurs at an h value of ⬃60 ␮m and M of Puppy 0.8 1.33 137
Cat 1.7 0.28 137
⬃2,000 kg. This suggests that very large animals with a Rabbit 2.3 0.22 137
relatively low breathing frequency have a thickness dur- Rabbit 2.2 0.20 19, 127
Rabbit 3.3 0.13 48, 177
ing breathing equal to that of apneic conditions. The adult Rabbit 3.7 0.09 207
elephant and whale fall into this category. In one study Dog 14 0.10 120
(53), the pleural space of an adult elephant was found to Dog 9 0.06 127
Dog 9 0.06 137
be filled with interstitial-like tissue, in contrast to the fetal

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elephant with a normal pleural space (67). The need to
breathe with the thorax submerged in water has been
proposed as the reason for the liquid-to-tissue transfor-
mation of the elephant’s pleural space (209). However,
anecdotal accounts describe the whale’s pleural space to
be similar to most mammals, except for the cranial region
where the pleural surfaces are fused (186).
2. Microvascular filtration
The relationship between pleural liquid thickness
and filtration was examined in spontaneously hyperten-
sive rats (100). Pleural liquid thickness measured in the
hypertensive rats was 40% greater than the thickness
measured in normotensive rats (10 ␮m). The increased
thickness together with a reduced pleural liquid protein
concentration was attributed to increased filtration
caused by the higher vascular pressure in the hyperten-
sive rats (45, 100).
Pig 24 0.04 137
Sheep 32 0.13 49, 212
2. Cell composition
Similar to interstitial liquid of other organs (34), pleu-
ral liquid contains protein (mainly albumin, globulin, and
fibrinogen) and a few cells (mainly mesothelial cells,
monocytes, and lymphocytes) (127, 177). Albumin (⬃50%)
comprises most of the protein followed by globulin
(⬃35%). The cell concentration found in dogs and rabbits
is ⬃2,000 cells/mm3 volume of pleural liquid. These cells
would occupy only ⬃1% of the pleural surface area. This
value was based on a mean cell radius of ⬃10 ␮m (196,
199), a lung surface area of 300 ␮m2 occupied by one cell,
a pleural liquid volume in rabbits of 0.4 ml (Table 2), and
lung surface area of 200 cm2 (127). Thus cells present in
pleural liquid would have a negligible effect on the force
balance across the pleural space and could not account
for the large contact stresses postulated.

3. Energy dissipation C. Microvilli: Spatial Distribution

The magnitude of the energy loss during breathing is
The pleural surfaces are lined by a layer of microvilli,
crucial to any theory of force transmission across the
1– 6 ␮m long depending on species and 0.1 ␮m thick (28,
pleural space. If only viscous losses due to sliding be-
29, 33, 115, 196). The physiological importance of mi-
tween uniformly spaced pleural surfaces were consid-
crovilli in relation to pleural liquid filtration and pleural
ered, a piston-in-cylinder model of the lung within the
lubrication, and the role of microvilli in reducing pleural
thorax would predict a power loss that is 1–2% of the
liquid shear stress, continue to be speculative. It is of
work of breathing (101). Much higher energy losses (35%)
interest that more microvilli are found in the caudal than
have been estimated due to frictional forces of pleural
in the cranial regions of the lung and chest wall surface
contact (47). Fluid lubrication affords the more efficient
(196), in parallel to the changes in lung-chest wall relative
mechanism for force transmission across the pleural sur-
velocity during ventilation (Fig. 4A). Microvilli have been
faces during breathing.
postulated to support contact forces between the pleural
surfaces, and thus account for part of the difference
B. Pleural Liquid Volume and Cell Composition between liquid and surface pressures (1, 2). Like the cells
in pleural liquid, the number of microvilli (average of 300
1. Pleural liquid volume per 100 ␮m2, Ref. 33) seems too small to occupy a signif-
icant contact area (⬃3% of the total area).
The volume of liquid collected from the pleural space
in several adult species is listed in Table 2. Pleural liquid D. Hyaluronan as a Pleural Lubricant
volume per unit body mass (Vpl) was found to decrease
with body mass (M) according the allometric equation: Hyaluronan has been identified as a coating on pleu-
Vpl ⫽ 0.39M⫺0.63 (n ⫽ 11, R2 ⫽ 0.68, P ⬍ 0.001). ral mesothelial cells (70, 107) and has been proposed as a

Physiol Rev • VOL 84 • APRIL 2004 • www.prv.org

394 STEPHEN J. LAI-FOOK
boundary lubricant (1, 2). A similar function has been
attributed to surfactant present in pleural liquid (80, 81).
The turnover of hyaluronan in the rabbit pleural space is
⬃1 day (30). Pleural liquid hyaluronan does not contrib-
ute to fluid lubrication because its concentration in pleu-
ral liquid (0.7 ␮g/ml) is too small to change pleural liquid
viscosity significantly from that of water (30). The amount
of hyaluronan present in the pleural tissue measured by
lavage in rabbits was 0.1 mg/kg body wt (207), consider-
ably greater than that present in the pleural liquid. Hya-
luronan in pleural liquid probably originates in the me-
sothelial cells and pleural tissue (207), although other
sources, such as lung liquid, are possible (51, 52).
The effect of ventilation on hyaluronan present in
pleural liquid was studied in anesthetized and conscious
rabbits (205). In conscious rabbits placed in a box, the
increase in hyaluronan concentration in pleural liquid
measured over 24 h was faster with a hypercapnic-in-
duced increase in ventilation than with room air ventila-
tion. In the anesthetized rabbits, hyaluronan concentra-
tion in pleural liquid doubled with a twofold increase in
ventilation. The increase in hyaluronan concentration was
attributed to an increase in the production of hyaluronan
from pleural tissue rather than to a washout effect of
increased filtration, an effect that has been demonstrated
in lung lymph studies (109). In studies of rabbits venti-
lated post mortem with no filtration, pleural tissue hyalu-
ronan doubled in conjunction with a 30% reduction of
pleural liquid volume (207). The increased hyaluronan
was attributed to the increase in pleural liquid shear
stress imposed on the mesothelial cells with a reduced
pleural liquid thickness. Because hyaluronan recovered
by lavage was ⬃1,000-fold greater than that present in the
normal pleural liquid, most of the increased hyaluronan
was probably sequestered within the tissue or trapped on
the mesothelial cell surface and between microvilli.
The role of hyaluronan in pleural lubrication remains
speculative. One proposal is that glycoprotein rich in
hyaluronan and enmeshed in microvilli (33) acts like a
boundary lubricant in the event of depletion of pleural
liquid. The unique properties of hyaluronan-rich solutions
(156) that resist motion at low shear rates but lower
viscosity and shear stress at high shear rates might be
crucial during breathing (1, 2). However, the shear mod-
ulus (⬃1 cmH2O) of hyaluronan solutions (156) seems too
small to support the large contact stresses that have been
postulated.
IV. CIRCULATION OF PLEURAL LIQUID
In the absence of pleural contact, gravity drives a
flow of pleural liquid downward in the pleural space.
Since all studies show a uniform pleural space thickness,
there must be a continuous redistribution of pleural liquid
Physiol Rev • VOL
from dependent to nondependent regions. A model of
pleural liquid recirculation has been proposed (54) with
the following elements: a gravity-dependent downward
flow of pleural liquid on the flat costal surfaces, an up-
ward flow along lobar margins, and a transverse flow from
lobar margins to the flat costal surfaces.
A. Gravity-Dependent Flows: Absence
of Hydrostatic Equilibrium
The forces driving flow downwards in the pleural
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space result from the vertical gradient in surface pressure
distribution determined by the opposing recoils of the
lung and chest wall and the force of gravity acting on the
pleural liquid. Consider steady unidirectional viscous flow
of liquid between the two pleural surfaces modeled as two
vertical parallel plates separated by thickness h. The fol-
lowing equation relating pressure (P) in the liquid to flow
(Q) downwards in the direction of gravity is known from
fluid mechanics (97, 98, 103)
␳ g ⫺ dP/dz ⫽ 12␯Q/共Lh3兲 (2)
where dP/dz is the gradient in pressure in the downward
z-direction, ␳g is the gravitational force per unit height
acting on the liquid, and L is the lateral dimension. The
left-hand side of Equation 2 represents the net force
driving flow downward. It is balanced by the term on the
right-hand side of Equation 2, the viscous pressure losses
due to flow per unit height. When the viscous losses are
negligibly small, Equation 2 reduces to dP/dz ⫽ ␳g, Pas-
cal’s law for a liquid at rest.
Consider the plates to be the lung and chest wall with
the opposing elastic recoils that produce a pleural surface
pressure gradient dP/dz. Because the compliance of the
lung and chest wall is relatively large and the pleural
space volume is extremely small, changes in pleural space
thickness have a negligible effect on the pleural surface
pressure. Thus the net pressure gradient, ␳g ⫺ dP/dz, is
unaffected by the flow or thickness. A change in flow
must therefore be accompanied by a change in thickness
to maintain the viscous pressure losses constant. For
example, in the prone position, where the pleural pres-
sure gradient (dP/dz) is zero, the viscous flow and pleural
space thickness adjust so that the viscous pressure losses
exactly balance the gravitational force on the liquid.
These conditions were simulated in a model of the pleural
space consisting of a cylindrical-shaped balloon ex-
panded within a rigid cylinder (102). Pleural pressure of
the model, equal to the balloon recoil, was uniform along
the height of the balloon, where the balloon was ex-
panded to a uniform diameter and the pleural space was
extremely thin, but varied by 1 cmH2O/cm height at the
two ends of the balloon, where the space was relatively
84 • APRIL 2004 • www.prv.org
 MECHANICS OF THE PLEURAL SPACE
wide and the balloon recoil was nonuniform. If the pleural
pressure gradient (dP/dz) were to equal 0.6 cmH2O/cm, as
measured in the supine position of many species (1, 2),
the net driving pressure would be 1 ⫺ 0.6 ⫽ 0.4
cmH2O/cm and the viscous losses would be 0.4
cmH2O/cm.
For a constant driving pressure, the flow (Q) depends
directly on h3. If h is halved, Q is reduced eightfold. Thus
the flow vanishes as the space thins to small values. In
Equation 2, the channel is assumed to be uniform in
thickness. However, as applied to the real pleural space,
nonuniformities in thickness may significantly increase
the flow resistance. For example, in the balloon-in-cylin-
der model of the pleural space (102), the measured flow
was two orders of magnitude less than that predicted for
a uniform channel. Thus nonuniformities in thickness
resulting in a vanishingly small pleural liquid flow might
explain in part why under apneic conditions the measured
pleural liquid thickness appeared to reach a minimum
value and was uniform with respect to height (102). The
presence of microvilli and cells in the pleural liquid would
also serve to increase flow resistance in the pleural space
(1, 2).
Other models of viscous flow within the pleural space
include the buoyancy forces exerted on a rigid chest wall
by a rigid lung of density lower than the pleural liquid (76,
77). This model predicts a vertical gradient in pleural
liquid thickness that is not supported by the uniform
thickness with height measured (7, 27, 101). The model of
Physiol Rev • VOL
395
the pleural space as a porous material (142) does not
match the physical characteristics of the pleural space,
except perhaps in the case of the adult elephant, whose
pleural space reportedly becomes filled with an intersti-
tial-like tissue (53).
B. Upward Flow Along Lobar Margins
Redistribution of pleural liquid from the lung base to
the upper regions of the pleural space occurs through the
widened pleural space formed at lobar margins. The pleu-
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ral liquid thickness profile measured by light microscopic
focusing (97) is shown in Figure 5, inset. Note that the
pleural space is considerably wider immediately adjacent
to the lobar margin, ⬃100 ␮m, and falls off monotonically
with distance from the margin to a value of 15 ␮m at the
costal surface. At lobar margins, the increased pleural
space ensures that viscous forces are negligible, resis-
tance to flow is small, and the vertical gradient in pleural
pressure approaches the hydrostatic value. The small flow
resistance is the reason why the distribution of an in-
jected bolus into the pleural space occurs primarily via
lobar margins (140). Studies in rabbits using fluorescent
microbeads (6 ␮m diameter) to visualize flow demon-
strated that cardiogenic and ventilatory motions act like a
pump to move pleural liquid upwards at lobar margins
while downward motion occurs on the costal surface
distant from the lobar margin (Fig. 5, Ref. 201).
FIG. 5. Upward (positive) and downward (nega-
tive) velocity of 6-␮m fluorescent latex microspheres at
lobar margins caused by cardiogenic motion. Inset
shows profile of pleural space measured in the vicinity
of a lobar margin by light microscopy in the rabbit. Note
that microspheres moved upward along the lobar mar-
gin where the pleural space was relatively wide and
downward where the pleural space was narrow. [Mod-
ified from Lai-Fook (97) and Wang and Lai-Fook (201).]
84 • APRIL 2004 • www.prv.org
396 STEPHEN J. LAI-FOOK
C. Transverse Flows: the Ventilatory Pump
Two studies using fluid mechanics to describe the
flow in thin channels have modeled recirculation of pleu-
ral liquid by ventilatory motion. In the first study (54), a
ventilatory pump moves liquid from lobar margins to the
flat costal surfaces in a direction that is opposite to what
occurs under apneic conditions due to the static pressure
gradient (Fig. 2). The analysis showed that pleural liquid
thickness (h) on the flat costal surface is related to lung
velocity amplitude (U) and the costal surface-to-lobar
margin pressure difference (⌬P)
h ⫽ 共T/⌬P兲共␯U/T兲2/3
where T is membrane tension. The prediction from Equa-
tion 3 was reproduced in a balloon-in-cylinder model of
the pleural space in conjunction with vertical strings to
simulate lobar margins. The thickness of the model’s
pleural space increased with velocity amplitude and de-
creased with the pressure difference. This behavior is
qualitatively consistent with in vivo studies that showed
pleural liquid thickness to increase with ventilation (Fig.
4A).
In the other study (96a), the change in thickness of a
fluid layer between two membranes with a local decrease
in spacing was studied in response to relative sliding of
the membranes. The presence of the decreased spacing
increases the local fluid pressure, which causes the mem-
branes to separate into a more uniform spacing. The
results suggest a mechanism based on ventilation-induced
shear stress to prevent contact between the two pleural
surfaces as the surfaces approach each other.
D. Fluid Volume Homeostasis
Homeostasis in pleural liquid volume considered
within the context of viscous flow concepts (97) comes
about by a matching of the microvascular filtration rate to
the flow within the pleural space. In the steady state,
microvascular filtration or pleural liquid flow equals the
outflow by lymphatic stomata. Pleural liquid flow that
results from gravity, for example, is related to pleural
liquid thickness through the viscous pressure losses that
balance the net driving pressure (Eq. 2). Any change in
filtration would result in a new equilibrium value for
pleural liquid thickness and pleural liquid volume (100).
This concept of homeostasis of pleural liquid volume
based on flow is different from that based on hydrostatics
(1, 2). According to homeostasis based on hydrostatics,
pleural capillaries absorb pleural fluid until there is con-
tact between the two pleural surfaces, at which point
pleural liquid pressure attains a hydrostatic equilibrium
and a minimal pleural liquid volume is reached.
Physiol Rev • VOL
The gravity-induced drainage of pleural liquid down-
ward in the pleural space also ensures that any excess
liquid accumulates in the most dependent part of the
pleural space, which is the dependent part of the costo-
phrenic sulcus forming the zone of apposition of the rib
cage to the diaphragm (119). This excess fluid does not
directly participate in lubrication of the lung surface and
has no effect on regional ventilation.
V. MICROVASCULAR EXCHANGE
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A. Pleural Anatomy and Blood Supply
(3)
The parietal and visceral pleura have a common ori-
gin during development (75). The structure of pleura is
that of extracellular matrix, including collagen and elastic
fibers (157), covered by a layer of mesothelial cells. Me-
diastinal pleura and pericardium are continuous with pa-
rietal and visceral pleura and in part are free standing.
The free-standing parts have two layers of mesothelial
cells.
McLaughlin et al. (116) classified mammals into three
groups according to their visceral pleural thickness.
Those with thick pleura include the pig, sheep, and cow.
Those with intermediate thickness include the horse and
human. Those with thin pleura include the mouse, rat,
rabbit, cat, and dog. In the sheep, the visceral pleural
thickness ranges from 25 ␮m in the cranial regions to 85
␮m on the diaphragmatic surface (28). This spatial varia-
tion might be related to movement with breathing (186) in
view of the cranial-caudal gradient in lung-chest relative
velocity measured in rabbits (Fig. 4B). In sheep, the pari-
etal pleura is of fairly constant thickness, 23 ␮m (29). In
humans it is 30 – 40 ␮m (167).
The blood supply to the visceral pleura depends on
its thickness group. The thin visceral pleura of the small
mammals have a pulmonary circulation. Intermediate and
thick visceral pleura of the larger mammals have a bron-
chial (systemic) circulation (65). The drainage of the
bronchial circulation occurs via the veins of the pulmo-
nary circulation (38). In the sheep, the blood supply is
located 10 –15 ␮m from the parietal pleural surface (29).
B. Transport Equations: Starling and Solute
Flux Equations
Pleural liquid originates from pleural capillaries
through the normal processes of microvascular filtration,
similar to those that occur in other organs (34, 185, 190).
Transport of pleural liquid and protein occurs across two
barriers, the capillary endothelium in series with the pleu-
ral interstitium (membrane). The location of the capillary
within the pleural membrane in relation to the pleural
84 • APRIL 2004 • www.prv.org
 MECHANICS OF THE PLEURAL SPACE
space is illustrated schematically in Figure 6. As in other
organs, the endothelium provides the major flow resis-
tance and restriction to protein. However, the relative
contribution of the interstitium to the overall barrier prop-
erties is still debated. Pleural membrane transport prop-
erties are summarized within a framework of two phe-
nomenological equations, the Starling equation and the
solute flux equation. Both equations are commonly used
to describe the transport of liquid and solutes across
biological membranes (60). The transport constants of the
two equations derived for the two-membrane system are
used to separate the contribution of the pleural intersti-
tium from the combined endothelium-interstitial barrier
properties.
1. The Starling equation
The Starling equation (184) relates the filtration rate
(Qb) across the capillary endothelial barrier in series with
the pleural membrane (interstitium) to the hydrostatic (P)
and protein (colloid) osmotic pressure (␲) difference be-
tween capillary blood and pleural liquid
Q b ⫽ LA关共Pc ⫺ Ppl兲 ⫺ ␴o共␲c ⫺ ␲pl兲兴
where subscripts c and pl refer to microvasculature and
pleural liquid, respectively, L is hydraulic conductivity, A
is surface area, and ␴o is the reflection coefficient to
protein of the combined endothelial-interstitial barrier.
LA is the filtration coefficient.
2. The solute flux equation
The mass flux of a solute (Qs) across the endothelial-
interstitial barrier is given by the solute flux equation
(60, 190)
Physiol Rev • VOL
397
Q s ⫽ C m 共1 ⫺ ␴ d 兲Q b ⫹ DA共Cc ⫺ Cpl兲/l (5)
where Cm is the mean solute concentration in the mem-
brane, ␴d is the solute drag reflection coefficient, D is
apparent diffusion coefficient, A is total membrane sur-
face area, l is membrane thickness, and C is solute con-
centration. For the flow of a single solute, ␴o equals ␴d
(173). The first term on the right-hand side of Equation 5
describes the solute flux due to bulk flow given by the
Starling equation (Eq. 4), while the second term describes
the solute flux due to diffusion.
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C. Hydraulic Conductivity, Reflection Coefficient,
and Diffusive Permeability
1. Hydraulic conductivity
Since the flow across the endothelium and intersti-
tium are in series, their flow resistances (inverse of con-
ductivity) add (assuming ␴o⌬␲ ⫽ 0 in Eq. 4)
1/L o ⫽ 共1/Lc兲 ⫹ 共1/Li兲 (6)
(4)
where subscripts o, c, and i refer to overall, endothelial,
and interstitial parameters, respectively.
Table 3 lists values of hydraulic conductivity (L)
measured for the endothelial-interstitial barrier of the
visceral pleura of dog lungs and values of visceral pleura,
parietal pleura, mediastinal pleura, pericardium, and dia-
phragm measured in a variety of species. The pericardium
and diaphragm are considered alongside the other pleural
membranes because they are parts of a continuous sac
lining the chest cavity, while the mesentery has morpho-
logical and transport properties similar to pleura.
FIG. 6. Schematic diagram of the path-
ways for normal pleural liquid turnover. In all
mammals, pleural liquid is mainly a filtrate
from capillaries in the parietal pleura lining the
chest wall (left). Arrows indicate direction of
flow. In large animals with thick visceral
pleura, some pleural liquid is filtered from the
bronchial capillaries of the visceral pleura lin-
ing the lung (bottom right). In small animals
with thin visceral pleura, a small amount of
pleural liquid might be reabsorbed by pulmo-
nary capillaries (top right). Drainage of pleural
liquid from the pleural space occurs via lym-
phatic stomata in the parietal pleura. The pleu-
ral space, visceral pleura, and alveoli are
thicker in large animals than in small animals.
84 • APRIL 2004 • www.prv.org
398 STEPHEN J. LAI-FOOK

TABLE 3. Hydraulic conductivity

Tissue Species Thickness, ␮m L K Reference Nos.

Visceral pleura Sheep 80* 1.6 1.3 92

Visceral pleura Dog 15† 39 5.9 164
Parietal pleura Dog 15† 190 29 164
Parietal pleura Dog 15† 2.6 0.38 153
Parietal pleura (in situ) Dog 15† 0.4 0.06 154
Parietal pleura (in situ) Dog 15† 0.3 0.045 155
Parietal pleura (in situ) Rabbit 13‡ 0.6 0.078 155
Mediastinal pleura Pig 130 20 21 162
Pericardium Human 550 0.75 4.1 69
Pericardium Dog 150 1.6 2.4 69
Pericardium Rabbit 30 2.8 0.85 165

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Pericardium Dog 150 3.0 4.5 165
Pericardium Pig 400 0.4 1.7 217
Pericardium Rabbit 32 0.6 0.2 145
Diaphragm Rat 600 0.4 2.4 143
Mesentery Rabbit 32 90 27 163
Capillary/visceral pleura Dog 0.5 14
Capillary/visceral pleura Dog 0.03§ 64
Capillary/visceral pleura Dog 1.1 93
Capillary/visceral pleura Dog 0.57 94
Capillary/visceral pleura Dog 0.50 95
Single capillaries Many 1 0.1–6 0.001–0.06 121

L, flow (cm3/s) per unit ⌬P (cmH2O) per unit surface area (cm2), expressed in 10⫺6 cm 䡠 s⫺1 䡠 cmH2O⫺1; K, L ⫻ thickness (cm), 10⫺8 cm2 䡠
s⫺1 䡠 cmH2O⫺1. * Data from costal part of caudal lobe (28). † Data from Payne et al. (164). ‡ Data from Lai-Fook and Kaplowitz (101).
§ Order of magnitude estimate.

Studies by Kinasewitz and co-workers (164) showed
that the overall conductivity measured in the whole lung
was much smaller than interstitial conductivity measured
in vitro (94). Thus the endothelial conductivity is almost
equal to the overall conductivity, and the resistance to
flow from the capillaries to the pleural space is predom-
inantly caused by the endothelium (Eq. 6). Almost the
entire pressure drop occurs across the endothelium, and
thus interstitial pressure is virtually equal to pleural liquid
pressure.
Membrane thickness varies from 15 ␮m for the dog
pleura (101) to ⬃80 ␮m for the sheep visceral pleura (28)
and giant rabbit pericardium (42, 43) to 130 – 400 ␮m for
the pig mediastinal pleura (162) and pericardium (217).
Therefore, for comparison purposes, the appropriate
measure of conductivity is K ⫽ L ⫻ l. K is then the flow
per unit area per unit pressure gradient (⌬P/l), whereas L
is flow per unit area per unit pressure difference. In the in
vitro studies, a piece of tissue was mounted between two
chambers in an Ussing-type apparatus. The flow of Ringer
solution across the membrane was measured in response
to a hydrostatic pressure difference. Measurements of
visceral and parietal pleura required stripping the mem-
brane from the lung and rib cage, respectively, a proce-
dure that has been criticized on the grounds that it causes
trauma to the tissue. Mediastinal pleura, pericardium,
diaphragm, and mesentery are free standing, and no strip-
ping was required for the in vitro studies. In in situ stud-
ies, a capsule was bonded to a pleural window made by
dissection of intercostal muscle and endothoracic fascia.
Flow across the pleura into the capsule from the pleural
space was measured as intracapsular pressure was var-
ied.
In general, the results of hydraulic conductivity (K)
fall into two groups: values of relatively high conductivity
(0.2–29 ⫻ 10⫺8 cm2䡠s⫺1䡠cmH2O⫺1) and values of an order
of magnitude smaller conductivity (⬃0.05 ⫻ 10⫺8
cm2䡠s⫺1䡠cmH2O⫺1). The high conductivity values were as-
sociated with in vitro measurements of parietal (164, 153),
visceral (92), and mediastinal pleura (162), diaphragm
(143), and pericardium (69, 145, 165, 217). Parietal and
visceral pleural membranes that were stripped from the
chest wall and lung, respectively, produced values similar
to those of free-standing mediastinal and pericardial
membranes. Thus trauma caused by stripping was un-
likely the reason for the high conductivity values. A sim-
ilar conclusion applies to the effect of stripping on reflec-
tion and diffusion coefficients (see below). Similar values
for hydraulic conductivity were obtained for pig pericar-
dium with mesothelial layers removed (217) and for dog
(69, 165), human (69), and rabbit (165) pericardium with
intact mesothelium. Thus the mesothelial layers were not
the major contributor to the measured conductivity.
The low hydraulic conductivity values were associ-
ated with the in situ studies. In these studies, the resis-
tance to flow into the capsule might have been artifactu-
ally increased by the thinning of the pleural space beneath
the capsule as the negative pressure in the capsule was

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 MECHANICS OF THE PLEURAL SPACE 399

transmitted to the lung. The lower parietal pleural con-
ductivity (0.05– 0.08 ⫻ 10⫺8 cm2䡠s⫺1䡠cmH2O⫺1) measured
in situ was about the same as the highest value measured
for the endothelium (0.001– 0.06 ⫻ 10⫺8 cm2䡠s⫺1䡠cmH2O⫺1)
and indicated a significant pressure drop across the inter-
stitium. This behavior was supported by parietal intersti-
tial pressure measured by cannulas and micropuncture
that showed a 2– 6 cmH2O interstitial-to-pleural liquid
pressure difference (129, 150); that is, 10 –20% of the total
pressure drop was assigned to the interstitium (133).
In summary, the results of the conductivity studies
showed that most (⬎80%) of the flow resistance of the
capillaries (0.9). Thus, on this basis, the endothelium is
the primary barrier to the transport of protein into the
pleural space.
Because the reflection coefficient of the endothe-
lium is greater than that of the interstitium, for any
value of Lc/Li, the overall reflection coefficient is less
than the endothelial reflection coefficient (Eq. 8).
Equation 8 shows that for Lc ⬍⬍ Li, ␴o tends to ␴c, and
for Lc ⬎⬎ Li, ␴o tends to ␴i. Thus a small interstitial
reflection coefficient always reduces the overall reflec-
tion coefficient of the endothelial-interstitial barrier

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from the value for the endothelium. For example, for an
pleural endothelial-interstitial barrier was associated with
interstitial reflection coefficient of 0.2, endothelial-to-
the capillary endothelium.
interstitial conductivity ratio of 0.1 and endothelial re-
flection coefficient of 0.9, the overall reflection coeffi-
2. Reflection coefficient
cient is reduced to 0.68.
The protein osmotic pressure exerted across the cap- Reflection coefficients near zero were measured in in
illary endothelium and pleural interstitium depends on vitro studies of both stripped dog parietal pleura (153,
the overall reflection coefficient of the two components. 164) and free-standing pig mediastinal pleura (162). Val-
From the Starling equation (Eq. 4) with ⌬P ⫽ 0 and A ues of reflection coefficient measured in rat diaphragm
constant (143) and rabbit pericardium (145) decreased from 0.3–
0.5 with Ringer solution to 0.15 with an albumin concen-
1/共L o␴o兲 ⫽ 1/共Lc␴c兲 ⫹ 1/共Li␴i兲 (7) tration of 1–2 g/dl. In the mesentery (163) and mediastinal
pleura (162), reflection coefficients (0.02– 0.14) increased
With the use of Equation 6 with flow. Thus differences in both albumin concentration
and flow might be responsible for the variability in the
␴ o / ␴ c ⫽ 共1 ⫹ L c/Li兲/关1 ⫹ 共Lc/Li兲共␴c/␴i兲兴 (8) reflection coefficients among the studies.
In the in situ studies (155), the albumin reflection
Table 4 lists albumin reflection coefficients of pleural coefficients of the parietal pleural interstitium, 0.3 in the
membrane (interstitium) measured in several species. dog and 0.4 in the rabbit, were greater than the in vitro
The measured interstitial reflection coefficients (0 – 0.5) measurements. These higher values would lower the over-
are much smaller than those measured for the capillary all reflection coefficient of the endothelial-interstitial bar-
endothelial-interstitial barrier (0.61– 0.93) and for single rier (Eq. 8), reduce the protein osmotic pressure gradient
opposing filtration, and increase the net filtration pressure
into the pleural space. Applied to the visceral pleura, a
TABLE 4. Albumin reflection coefficients (␴) small interstitial reflection coefficient would reduce any
reabsorption from the pleural space.
Reference
Tissue Species ␴ Method Nos. In experiments using intercostal capsules bonded to
parietal pleura of rabbits (155), the transport of labeled
Parietal pleura Dog 0 Excised tissue 164
Parietal pleura Dog 0.11 Excised tissue 153
macromolecules from pleural liquid to the parietal pleural
Parietal pleura Dog 0.4 In situ 155 capsule was consistent with two sets of pores in the
Parietal pleura Rabbit 0.3 In situ 155 parietal pleura, 8.5 and 19 nm. Based on the theory of
Mediastinal pleura Pig 0.02–0.05* Excised tissue 162
Pericardium Rabbit 0.42 Excised tissue 165 restriction of solutes through cylindrical pores (60), the
Pericardium Rabbit 0.1–0.3† Excised tissue 145 smaller pore is consistent with an interstitial reflection
Diaphragm Rat 0.1–0.5† Excised tissue 143 coefficient of 0.4, similar to the value found in rabbit lung
Mesentery Rabbit 0.02–0.14* Excised tissue 163
Capillary/visceral interstitium (195) and rat diaphragm (143) for low albu-
pleura Dog 0.61–0.93 In situ: lung in bag 94 min concentrations.
Capillary
endothelium Many 0.9 Single capillaries 121 In summary, all studies showed reflection coeffi-
cients that were smaller for the interstitium than for the
* Reflection coefficient increased with flow. † Reflection co- endothelium. Thus restriction of protein by the pleural
efficient decreased with albumin concentration measured using flow-
independent sieving ratio. All other studies used osmotic transient capillary endothelial-interstitial barrier was largely asso-
method. ciated with the endothelium.

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400 STEPHEN J. LAI-FOOK

3. Diffusive permeability
Table 5 summarizes albumin permeability and diffu-
sion coefficients measured in a variety of tissue mem-
branes of several species. Permeability is the parameter
required to estimate the relative contribution of pleural
interstitium and capillary endothelium to the overall en-
dothelial-interstitial barrier. Permeability (Pe) is equal to
diffusion coefficient divided by membrane thickness
(D/l). The overall permeability (Peo) is related to intersti-
tial (Pei) and endothelial (Pec) permeability, with the as-
sumption of zero bulk flow and constant surface area (A,
diffusion coefficients are usually associated with the ex-
tracellular matrix because nearly similar values were ob-
tained from a wide range in tissue thickness (30 – 600 ␮m).
In contrast, diffusive permeability measured in pericar-
dium has been attributed to the mesothelium because
scraping the mesothelium from the tissue increased per-
meability 10-fold (43). However, the scraping might also
have increased tissue permeability.
In vitro values of albumin diffusion coefficient (0.4 –
22 ⫻ 10⫺8 cm2/s) were two orders of magnitude greater
than the in situ values (2–12 ⫻ 10⫺10 cm2/s). Diffusion
coefficients might be somewhat greater in the in vitro

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Eq. 5), as follows
1/Pe o ⫽ 1/Pec ⫹ 1/Pei
If interstitial permeability were much greater than
endothelial permeability, the overall permeability would
almost equal endothelial permeability, and the major dif-
fusive resistance would be associated with the capillary
endothelium. That the endothelium dominates the overall
barrier to diffusion was supported by permeability values
of the capillary-interstitial barrier of the visceral pleura
measured in perfused dog lungs (94, 95) that was two
orders of magnitude smaller than that of visceral pleural
interstitium (164). In contrast, the permeability of parietal
pleura measured in rabbits by intercostal capsules was
lower (155) than that measured for the endothelial-inter-
stitial barrier of dog visceral pleura (94, 95). This implied
that the pleural interstitium contributed the major resis-
tance to the diffusion of albumin across the endothelial-
interstitial barrier.
Almost all data of the in vitro studies (Table 5) sup-
port a relatively small contribution of interstitial diffusive
resistance to the overall diffusive resistance. Because the
pleural membrane thickness varies considerably among
species, diffusion coefficient D ⫽ Pe ⫻ l is the appropriate
parameter for comparison among species. The measured
studies because isolated tissue immersed in solution al-
ways increases hydration spontaneously by ⬃50% (56,
(9) 143).
Diffusion of albumin in mediastinal pleura (162) and
rat diaphragm (143) increased with concentration. This
behavior is consistent with the reduced reflection coeffi-
cient measured with an increase in albumin concentration
and implies an enhanced absorption of interstitial albu-
min under conditions of increased microvascular perme-
ability.
In summary, the results of most studies showed that
the diffusive resistance to protein was much smaller for
the interstitium than for the endothelium. This indicated
that the major barrier to diffusion was associated with the
endothelium.
D. Pleural Filtration Pressure and Filtration and
Absorption Rates
1. Pleural filtration pressure
Whether the Starling force balance across the pleural
microvascular barrier favors filtration or reabsorption is
still debated, with the evidence strongly in favor of an
overall net filtration into the pleural space. There is a
general consensus that pleural liquid is a microvascular

TABLE 5. Albumin permeability and diffusion coefficients

Tissue Species Thickness, ␮m Pe, 10⫺6 cm/s D, 10⫺8 cm2/s Reference Nos.

Visceral pleura Dog 15* 34 4.4 164

Parietal pleura Dog 15* 130 20 164
Parietal pleura Dog 15* 10 1.5 153
Parietal pleura (in situ) Dog 15* 0.8 0.12 154
Parietal pleura (in situ) Rabbit 13† 0.15 0.02 155
Mediastinal pleura Pig 130 2.3 3 162
Pericardium Rabbit 30 73 22 165
Pericardium Rabbit 32 1.3 0.4 144
Pericardium Rabbit 70 0.9 0.63 42, 43
Diaphragm Rat 600 0.75 6 143
Capillary/visceral pleura (lung) Dog 2.4 94
Capillary/visceral pleura (lung) Dog 4.3 95

Permeability coefficient (Pe) ⫽ diffusion coefficient (D)/thickness. * Data from Payne et al. (164). † Data from Lai-Fook and Kaplowitz
(101).

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 MECHANICS OF THE PLEURAL SPACE 401

filtrate from the parietal pleural capillaries. The debate
centers on the contribution of visceral pleural capillaries
and interstitial lymphatics to the absorption of pleural
liquid and protein.
Table 6 shows the values of the Starling forces used
to evaluate the net filtration pressure published in several
reviews (18, 133, 186) and other sources (100). The values
for parietal pleura and visceral pleura are listed sepa-
rately. Hydrostatic pressures in the microvasculature
(capillary) and pleural space are given for midlung height.
Since capillary pressure varies as 1 cmH2O/cm height,
whereas pleural pressure is uniform for the normal prone
are minimal estimates since respiration reduces the pleu-
ral pressure below the values used at end-expiration.
The forces favoring filtration or reabsorption in the
visceral pleura are arguable because the blood supply to
the visceral pleural capillaries has a systemic source in
the larger mammals, including humans, but a pulmonary
source in smaller mammals (116). Although a systemic
(bronchial) circulation supplies the visceral pleura of the
larger mammals, the bronchial arteries drain into the
pulmonary veins (65) and the magnitude of the pressure
in the visceral pleural capillaries is somewhat uncertain.
Accordingly, in the visceral pleura, a net filtration pres-

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posture, the hydrostatic pressure difference across the
barrier would be reduced in nondependent regions and
increase in dependent regions.
The effective protein osmotic pressure difference
across the endothelial-interstitial barrier, ␴o(␲c ⫺ ␲pl),
favoring plasma retention of liquid varies from 23 cmH2O
in sheep (186) and dog (18) to 10 –13 cmH2O in the rat
(100) and rabbit (133). The value of ␴o used (⬃0.9) was
appropriate for the endothelium (121). The smaller values
of protein osmotic pressure difference across the endo-
thelial-interstitial barrier are mainly due to relatively high
values of protein colloid osmotic pressure for pleural
liquid coupled with relatively low values for blood plasma
measured in the smaller mammals. These estimates of
protein osmotic pressure difference are maximal, since
any significant reflection coefficient and hydraulic con-
ductivity for the interstitium would reduce the overall
reflection coefficient and osmotic pressure difference for
the total barrier (see sect. VC2).
The parietal pleura has a systemic circulation, and its
capillary pressure ranges from 17 to 34 cmH2O. Pleural
pressure at end-expiratory lung volume varies from ⫺2 to
⫺4 cmH20 (1, 2). The hydrostatic pressure difference
(Pc ⫺ Ppl) favoring filtration has a range of 21 cmH2O in
the rabbit (133) to 31 cmH2O in the rat (100), which
together with a 10 –23 cmH2O osmotic pressure difference
opposing filtration, produces a net filtration pressure
[(Pc ⫺ Ppl) ⫺ ␴o(␲c ⫺ ␲pl)] of 8 –21 cmH2O. These values
sure similar to that for the parietal pleura (9 cmH2O) is
calculated for a systemic source in sheep (186) and for a
pulmonary source in the rat (11 cmH2O). In contrast, a
zero or net absorptive pressure is calculated for a pulmo-
nary source in the sheep (186), dog (18), and rabbit (133).
However, the magnitude of the net absorptive pressure
(⬃0 to ⫺4 cmH2O) into the visceral pleura is much
smaller than the net filtration pressure (8 –21 cmH2O)
from the parietal pleura, which by itself indicates an
overall net filtration into the pleural space of all species.
The lower pleural pressure with breathing would reduce
the small absorptive pressure in the visceral pleura esti-
mated at end-expiratory lung volume (sheep and rabbit).
Net filtration pressure by itself is not sufficient to
determine whether net filtration or absorption occurs
from the parietal and visceral pleural membranes because
filtration is the product of hydraulic conductivity and net
filtration pressure (Eq. 4). Given about the same hydraulic
conductivity for visceral and parietal pleura (Table 3) and
the same blood flow in both pleura, the much larger net
filtration pressure for the parietal pleura compared with a
smaller net absorptive pressure for the visceral pleura
would support an overall net microvascular filtration into
the pleural space. An exception in the data (Table 3) is the
parietal pleural hydraulic conductivity measured with in-
tercostal capsules (154, 155) that is 1–2 orders of magni-
tude smaller than that measured in the other studies and
similar to that of the visceral pleural endothelium-inter-

TABLE 6. Filtration pressures (cmH2O) for parietal and visceral pleura

Species Pc Ppl Pc ⫺ Ppl ␴o ␲c ␲pl ␴o(␲c ⫺ ␲pl) Net Reference Nos.

Parietal pleura
Sheep 28 ⫺9 37 0.9 30 4 23 14 186
Rabbit 17 ⫺4 21 0.8 25 8 13 8 133
Rat 34* ⫺3 37 0.9 20 9 10 21 100
Visceral pleura
Sheep (systemic) 23 ⫺9 32 0.9 30 4 23 9 186
Sheep (pulmonary) 11 ⫺9 20 0.9 30 4 23 ⫺3 186
Rabbit 10 ⫺4 14 0.7 28 8 14 0 133
Rat 14 ⫺3 17 0.9 17 10 6 11 100
Dog 10 ⫺9† 19 0.9 29 3 23 ⫺4 18

Net ⫽ [(Pc ⫺ Ppl) ⫺ ␴o(␲c ⫺ ␲pl)]. ␲c is derived from protein concentration using Landis and Pappenheimer’s equation (106). * Data from
Bohlen et al. (45). † Data are mean pressure during breathing cycle (18).

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402 STEPHEN J. LAI-FOOK

stitial barrier. However, the low parietal pleural conduc-

tivity is offset by a relatively high interstitial reflection
coefficient (Ref. 155; Table 4) that would reduce the os-
motic retention by plasma and increase filtration.
The absorption of water from the pleural space into
the lung visceral pleural capillaries (93) was observed
with the appropriate manipulation of the Starling forces
(Eq. 4). In contrast, with pulmonary edema, lung edema
crossed the visceral pleura into the pleural space (52, 213)
because the pressure in lung interstitium is above the
pleural pressure (41, 68, 71, 72).
Physiological studies have provided evidence that

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the source of pleural liquid is the systemic capillaries of
the parietal pleura. Mellins et al. (120) elevated systemic
and pulmonary venous pressure separately or together in
dogs and found that the accumulation of pleural liquid
was much larger with systemic than with pulmonary ve-
FIG. 7. Ratio of total protein concentration in pleural liquid to that
nous hypertension. Further evidence for a parietal source in plasma (Cpl/Cc) versus body mass (M) in several species. Note that
of pleural liquid is that the pleural effusions produced by Cpl/Cc decreases with body mass, according to the allometric relation-
an increased pulmonary venous pressure in dogs were ship (solid line): Cpl/Cc ⫽ 0.34 M⫺0.23 (R2 ⫽ 0.78, n ⫽ 16, P ⫽ 7 ⫻ 10⫺6).
[Modified from Lai-Fook (97).]
derived from pulmonary edema and not from the capillary
hypertension of the visceral pleura (31).
Other physiological evidence supports the conclu-
Interstitial protein concentration measured in the pa-
sion that there is an overall net microvascular filtration
rietal pleura of rabbits by implanted wick catheters (148)
into the pleural space. First, tracer studies showed that
was 2.6 g/dl, somewhat smaller than that in pleural liquid
pleural liquid and solute absorption were primarily asso-
(3.1 g/dl). The calculated interstitial-to-pleural liquid pro-
ciated with lymphatic stomata on the parietal pleural
tein osmotic pressure difference was 3.5 cmH2O or 27% of
surface with little evidence for visceral pleural absorption
the total difference between the capillary and pleural
(28, 29, 40, 50, 58, 59, 206). Second, imaging studies indi-
liquid (13 cmH2O). The interstitial-to-pleural liquid hydro-
cated that lymphatic absorption increased toward the
static pressure difference measured by micropuncture
caudal regions where the lymphatic stomata are concen-
was 1.8 cmH2O (129). These differences in protein os-
trated (152). Third, anatomic and morphological studies
motic pressure assigned to the parietal pleural membrane
in sheep showed that the microvessels in the parietal
can be questioned because of the uncertainty of the loca-
pleura were located 15 ␮m from the pleural surface (29),
tion of the wick used for collecting the interstitial liquid
whereas the microvessels in the visceral pleura were
(18). In spite of the objections, the small differences in
located much deeper (20 –50 ␮m; Ref. 28). Accordingly, in
hydrostatic and protein osmotic pressures do not substan-
sheep hydraulic conductance from the pleural space to
tially change the overall net filtration pressures and thus
the microvessels would be less in the visceral than in the
do not invalidate the assumption that protein concentra-
parietal pleura, and filtration from or reabsorption into
tion of pleural liquid largely reflects that of the microvas-
the visceral pleural capillaries would be inhibited. Thus
cular filtrate.
pleural anatomy, at least in sheep, supports the physio-
In summary, the pathways for normal pleural liquid
logical evidence that pleural liquid filtration occurs via the
turnover are illustrated schematically in Figure 6. Pleural
parietal pleura (186). However, in the smaller mammals
liquid is derived mainly from capillaries in the parietal
with a visceral pleura similar in thickness to the parietal
pleura lining the chest wall of all mammals. Some pleural
pleura, any reabsorption of pleural liquid into visceral
liquid is filtered from bronchial capillaries in the thick
pleural capillaries with a high reflection coefficient would
visceral pleura of large mammals. Pleural liquid is re-
concentrate pleural liquid protein and perhaps account
moved by lymphatic stomata in the parietal pleura. A
for the greater protein concentration in the smaller mam-
small reabsorption of pleural liquid might occur into the
mals (see sect. VI, Table 8, Fig. 7). Finally, reabsorption of
pulmonary capillaries of the thin visceral pleura of the
pleural liquid by the lung interstitium, though possible, is
smaller animals.
unlikely in view of subpleural interstitial pressures that
were slightly (1 cmH2O) above the pleural pressure (41,
2. Filtration and absorption rates
68, 71, 72). These results contrast to a negative lung
interstitial pressure of ⫺10 cmH2O measured in situ at Table 7 summarizes the pleural liquid filtration and
locations 200 ␮m below the pleural surface (134, 135). absorption rates estimated in several species. The esti-

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 MECHANICS OF THE PLEURAL SPACE 403

TABLE 7. Pleural liquid filtration and absorption rates

Species Rate, ml 䡠 h⫺1 䡠 kg⫺1 Method Reference Nos.

Rabbit 0.017 Catheter drain 48

Dog 0.020 Tracer kinetics and lymph clearance 124
Dog 0.019 Imaging of tracer in ⬃1 ml hydrothorax 152
Sheep (awake) 0.01 Tracer kinetics into pleural space from blood 212
Rabbit 0.22* 2 ml hydrothorax 136
Rabbit 0.22* 1 ml hydrothorax 15
Dog 0.57* 12 ml/kg hydrothorax 188
Dog 0.47‡ 12 ml/kg hydrothorax 188
Sheep (anesthetized) 0.02† Tracer in lymph, 10 ml/kg hydrothorax 212
Sheep 0.22* 10 ml/kg hydrothorax 212
Sheep 0.28* 10 ml/kg hydrothorax 52

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Human 0.36* Heart failure/malignant effusions 187
Human 0.11* Effusions 110

* Absorption rate was calculated from the volume of hydrothorax recovered. † This value proved to be a gross underestimate by a
subsequent study (52). ‡ Filtration rate.

mated filtration rate measured without hydrothoraces
scales approximately to body weight. In unanesthetized
sheep, the appearance in pleural liquid of tracer 125I-
albumin injected into the blood produced a protein filtra-
tion rate of 0.01 ml䡠h⫺1䡠kg⫺1 (212). Somewhat greater
values (0.02 ml䡠h⫺1䡠kg⫺1) for pleural filtration have been
estimated in the dog (124, 152) and rabbit (48). In con-
trast, studies using large hydrothoraces produced much
higher pleural liquid absorption rates (0.11– 0.57
ml䡠h⫺1䡠kg⫺1) in sheep (50, 212), rabbits (15, 136), dogs
(188), and humans (110, 187). Thus, with large hydrotho-
races, absorption of pleural liquid can increase 10- to
30-fold above the normal turnover rate (18, 50, 125, 126,
133, 186). Accordingly, absorption of large hydrothoraces
is not a reliable measure of normal filtration into the
pleural space or of the normal turnover rate of pleural
liquid.
The volume of pleural liquid divided by the filtration
rate provides an estimate of the pleural liquid transit time,
that is, the time required to turnover the entire pleural
liquid volume. From values provided in Tables 2 and 7, the
turnover time for pleural liquid is 10 –13 h for rabbits and
sheep.
E. Regional Absorption, Role of Lymphatics,
and Regional Filtration
1. Regional absorption
Regional absorption of pleural liquid has been stud-
ied by histological identification and external imaging of
tracers injected into the pleural space. Anatomical studies
showed that absorption sites via lymphatic stomata are
concentrated in the ventral-caudal and dorsal-caudal re-
gions of the parietal pleura of the rib cage in sheep (29,
115) and rabbits (197) and in the diaphragm of rabbits
(151). Tracer studies showed that the visceral pleural
lymphatics do not participate in pleural liquid absorption
(50, 206). The concentration of lymphatic stomata in the
caudal regions of the pleural space was supported by
imaging studies in dogs, which showed a lower absorp-
tion rate of radioactive tracer from cranial regions than
from caudal and mediastinal regions (152). The distribu-
tion of lymphatic stomata concentrated in the intercostal
spaces rather than on the rib surfaces (29) was supported
by fluorescent studies that showed a greater absorption in
the intercostal muscle than in the rib (206).
2. Role of lymphatics
Lymphatic drainage from the pleural space occurs
via the stomata in the parietal pleura (29, 181). The ultra-
structure of stomata has been described in the parietal
pleura (108, 197) and the peritoneum (108). The mecha-
nism by which lymphatics absorb pleural liquid remains
speculative. One model postulated that the pleural liquid
pressure was set by the lymphatics and that the absorp-
tion rate was determined by the pressure-volume relation-
ship of the pleural space (141). As the volume of the
pleural space was reduced, the pleural liquid pressure and
the pressure gradient for lymphatic absorption decreased.
The pressure generated by parietal pleural lymphatics
was estimated to be ⫺7 cmH2O relative to pleural pres-
sure (138). This absorptive pressure for pleural lymphat-
ics is below the mean values (⬃0 cmH2O) measured in the
intercostal pleural lymphatics of rabbits (149) and in
other organs (179). However, the pressure associated
with the absorption of liquid via lymphatics might be
generated by cardiogenic and smooth muscle contractile
oscillations in conjunction with unidirectional valves
(146, 149, 179).
The postulate (130, 131) that an absorptive pressure
in pleural lymphatics below the pleural liquid pressure
determines the pleural liquid pressure seems unlikely
based on the following considerations. First, the distribu-

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404 STEPHEN J. LAI-FOOK

tion of lymphatic stomata even where they are most con-
centrated is sparse. In sheep (29), one stoma of 1–3 ␮m
diameter is found per 25 ⫻ 25 ␮m surface area. In the
rabbit diaphragm (151), one stoma is found per 60 ⫻ 60
␮m surface area. The primary mechanism for fluid ab-
sorption into lymphatic stomata from adjacent sites is
redistribution of pleural liquid by ventilatory and cardio-
genic motion, not a flow driven by a difference in hydro-
static pressure. Second, lymphatic stomata are concen-
trated in the caudal regions of the pleural space with few
in the cranial regions, a spatial distribution that is not
matched by a cranial-to-caudal difference in pleural liquid
showed a cranial-caudal gradient in filtration (206). Albu-
min filtration was lowest at the cranial ribs and increased
with rib number to reach a maximum at the seventh rib.
This cranial-caudal distribution matched the regional dis-
tribution of lymphatic absorption sites measured anatom-
ically (29, 197) and the regional distribution of an ab-
sorbed bolus (152). Perhaps not coincidentally, the cra-
nial-caudal gradient in filtration matched that in pleural
liquid thickness (Fig. 4A). The cranial-caudal gradient in
protein filtration seems at odds with the uniform blood
flow measured in the parietal pleura in dogs by radioac-
tive microspheres (192).

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pressure.
Since the absorption rate of hydrothoraces is consid-
erably greater than the normal turnover rate of pleural
liquid, experiments using the absorption of hydrothoraces
comprising saline or plasma (136) do not provide reliable
evidence for lymphatic absorption under normal condi-
tions. Indeed, the results of these experiments proved to
be not reproducible (19). These results are difficult to
interpret because the changes in visceral pleural capillary
filtration with protein concentration of the hydrothorax
and in lymphatic absorption with the size of the hydro-
thorax are difficult to estimate. The concept that pleural
lymphatics can concentrate protein does not have direct
experimental support. The usual assumption based on
data from other organs is that lymphatics do not restrict
the passage of protein from interstitial liquid (34, 179).
3. Spatial variation in filtration
In contrast to the anatomic and physiological studies
of the pleural liquid absorption sites, there is a paucity of
studies of regional pleural liquid filtration. Fluorescence
of Evan’s blue-dyed albumin emitted from the parietal
pleura of rabbits 6 h after injection into the circulation
VI. PLEURAL LIQUID
PROTEIN CONCENTRATION
A. Effect of Body Size, Vascular Pressure,
Ventilation, and Regional Differences
The concentration of protein present in the pleural
liquid is important for the following reasons. First, it is
one of the variables in the Starling equation that deter-
mines filtration. Thus its changes with body size might
indicate differences in filtration and absorption of pleural
liquid. Second, changes in pleural liquid protein concen-
tration with ventilation might indicate shear stress-in-
duced changes in pleural membrane permeability. Third,
regional changes in protein concentration might indicate
regional changes in filtration.
1. Effect of body size
Table 8 lists values of pleural liquid-to-plasma (cap-
illary) protein concentration ratio (Cpl/Cc) from several
sources. Figure 7 is a plot of Cpl/Cc versus body mass.

TABLE 8. Pleural liquid-to-plasma total protein concentration ratio

Species Cpl, g/dl Cc, g/dl Cpl/Cc Weight, kg Reference Nos.

Rat 2.5 6.4 0.39 0.45 137

Rat (WKY) 2.4 4.3 0.55 0.27 100
Rat (SHR) 2.0 4.8 0.42 0.30 100
Cat 1.4 6.5 0.21 1.7 137
Dog (pup) 2.3 6.0 0.38 0.8 137
Rabbit 1.33 6.2* 0.21 2.2 127
Rabbit 1.4 6.2* 0.23 3.5 177
Rabbit 1.9 6.2 0.31 2.3 137
Rabbit 2.0 6.2 0.32 3.5 207
Rabbit 2.3 6.6 0.34 3.5 205
Sheep (fetus) 1.7 3.4 0.50 3.5 49
Sheep (newborn) 1.5 5.5 0.27 7.7 49
Dog 1.1 5.8 0.18 9 137
Dog 1.06 6.0* 0.18 11 127
Pig 1.2 6.3 0.19 24 137
Sheep (adult) 0.88 6.2 0.15 27 50
Sheep (adult) 0.96 6.2 0.15 28 212

Cpl, pleural liquid concentration; Cc, plasma total protein concentration. * Data from Miserocchi et al. (137).

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 MECHANICS OF THE PLEURAL SPACE
Experiments by Miserocchi et al. (137) in several mam-
malian species showed that Cpl/Cc decreased with an
increase in animal size. In sheep, where the vascular
supply to the visceral pleura is systemic rather than pul-
monary, Cpl/Cc is ⬃0.15 (50, 212). This low Cpl/Cc value
points to a microvascular barrier that is relatively imper-
meable to protein with a reflection coefficient approach-
ing 1.
2. Effect of vascular pressure
The decrease in Cpl/Cc with animal size has been
explained on the basis of a vascular-to-pleural difference
in hydrostatic pressure that increases with animal size
(137). This explanation is supported by two other obser-
vations. Studies in the spontaneously hypertensive rat and
its normotensive control rat showed that Cpl/Cc was re-
duced in the hypertensive rat, consistent with a wash-
down effect caused by a higher microvascular pressure
and greater filtration (100). A similar decrease in Cpl/Cc
occurred in sheep with development from the fetus to
adulthood as systemic vascular pressure increased with
age (49).
An alternative explanation for the decrease in Cpl/Cc
with animal size is that smaller mammals with a pulmo-
nary blood supply to the visceral pleura have a small net
absorptive pressure into the visceral pleural capillaries
that would increase the protein concentration in pleural
liquid. Another possibility is a change in pleural mem-
brane permeability with body size (97).
3. Effect of ventilation
In vitro studies of pleural mesothelial cells in culture
showed a viscous flow-induced increase in permeability
(208). Accordingly, the question whether an increased
ventilation-induced shear stress can increase pleural
membrane permeability to albumin was addressed in both
anesthetized and conscious rabbits (205). In the anesthe-
tized rabbits, an increase in mechanical ventilation for 6 h
resulted in an increase in Cpl/Cc measured using Evan’s
blue albumin injected into the circulation, consistent with
an increased permeability. However, subsequent studies
in conscious rabbits showed no change in pleural liquid
protein kinetics or systemic arterial pressure between
breathing either room air or a hypercapnic gas mixture
that increased ventilation. Thus the studies in conscious
animals did not confirm the increased permeability ob-
served in anesthetized animals and cultured cells.
4. Regional differences
In the absence of effective interregional mixing, a
consequence of a greater dependent microvascular pres-
sure and filtration would be a lower pleural protein con-
centration in the dependent regions of the thorax. Such a
Physiol Rev • VOL
405
behavior has been reported for pulmonary interstitial pro-
tein as measured in visceral pleural lymphatics (26) but
not for parietal pleural lymphatics. Studies in hyperten-
sive rats showed an increased pleural liquid thickness and
lower protein concentration with a hypertension-induced
increase in filtration (100). Thus the lower pleural liquid
thickness in the cranial region (Fig. 4A) in conjunction
with a lower protein filtration (206) suggests that a rela-
tively small filtration and a relatively high pleural liquid
protein concentration would be found in the cranial re-
gion.
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B. Active Protein and Solute-Coupled
Liquid Transport
1. Active protein transport
Studies (5, 42) reporting active transport of protein
by mesothelial cell vesicles have challenged the view that
the primary route of protein absorption from the pleural
space is via lymphatic stomata. The anatomy of the me-
sothelial cell does not exclude such a mechanism (39,
199). In vitro permeability studies of rabbit pericardium
showed a reduced diffusive transport of albumin and
dextran with the vesicular inhibitor nocodazole (42). Sub-
sequent studies in anesthetized rabbits suggested that the
vesicular inhibitor nocodazole reduced the absorption of
tracer albumin and dextran measured 3 h after injection
into the pleural space (5). However, in the latter study, the
effect of the inhibitor on macromolecular absorption
from the pleural space was measured with a hydrothorax,
a condition that increases the pleural liquid absorption
10-fold above normal (Table 7). Thus this method cannot
provide reliable information for normal conditions. Re-
cent attempts to reproduce the permeability studies in
rabbit pericardium showed an increased diffusion and
hydraulic conductivity by nocodazole (144, 145) rather
than a reduced transport. Moreover, other studies showed
an increased microvascular permeability in response to
vesicular inhibitors (55, 172). Thus mesothelial transcyto-
sis as a mechanism for pleural liquid protein transport
does not yet have conclusive supporting evidence.
2. Active liquid absorption
Studies in anesthetized rabbits (16 –18, 218 –224) and
in excised human (178) and sheep pleura (79, 178) pro-
vided indirect evidence of a solute-coupled liquid absorp-
tion from the pleural space. The results of these studies
have been summarized in a recent review (18). In the in
vitro studies, significant but small (⬃10%) increases in
electrical resistance were measured in response to Na⫹
and K⫹ transport inhibitors. There is a need to relate
these small changes in electric resistance to liquid trans-
port. In the in vivo studies, decreases in the absorption
84 • APRIL 2004 • www.prv.org
406 STEPHEN J. LAI-FOOK
rate of pleural liquid containing Na⫹ transport inhibitors
were extrapolated from values of the absorption rate with
0.5–5 ml hydrothoraces. A limitation of this approach is
that the rate of absorption of 1–2 ml hydrothoraces in
rabbits most likely overestimated the normal rate by 10-
fold (Table 7). Thus the contribution of active liquid ab-
sorption relative to that of lymphatic absorption remains
to be measured under normal conditions.
C. Clearance by Lymphatic Stomata Versus
Mesothelial Absorption
The steady-state pleural liquid protein concentration
is relatively low, consistent with microvascular filtration
with a high reflection coefficient and absorption via lym-
phatic stomata that do not restrict the passage of protein.
This rather simple explanation for the turnover of pleural
liquid contrasts to the more complex one needed if active
water and protein reabsorption by the mesothelium were
the primary mechanism of absorption. The evidence for
transcytosis of protein by mesothelium is inconclusive
(see sect. VIB). Even if protein were transported by trans-
cytosis, the subsequent route of absorption would be
problematic. One route, transcapillary reabsorption of
protein, seems improbable in view of a reflection coeffi-
cient of 0.7– 0.9 measured for pulmonary (190) and sys-
temic capillaries (121). Protein and water reabsorption by
the alternative route, interstitial lymphatics, although pos-
sible, seems unlikely since hydraulic conductance of in-
terstitium is considerably less than that of lymphatic sto-
mata. Furthermore, if the interstitial lymphatics were the
primary route of absorption, it would be difficult to ex-
plain how the microvascular filtrate from the parietal
pleural capillaries ever reaches the pleural space.
VII. CONCLUDING REMARKS
I have attempted to summarize the pertinent litera-
ture within the context of a view of pleural mechanics
based on viscous flow concepts as opposed to one based
on hydrostatic equilibrium and pleural contact. The con-
cept of fluid lubrication applied to the redistribution of
pleural liquid provides a more complete understanding of
the forces at work in the pleural space. However, there
are two areas in pleural research where our understand-
ing of the basic physiology is incomplete. The first is
related to pleural contact. In spite of the lack of direct
experimental evidence of pleural contact, the large
amount of hyaluronan produced by increased ventilation
suggests some role for hyaluronan as a boundary lubri-
cant to reduce shear stress on the mesothelial cell surface
and the power loss during breathing. Further work is
needed to resolve the relative contributions of boundary
and fluid lubrication. The second is related to pleural
Physiol Rev • VOL
liquid reabsorption. Although pleural liquid and protein
absorption via lymphatic stomata is the straightforward
way to explain the available data, the contribution of
active transport across the mesothelium to absorption
under normal conditions remains to be evaluated.
This research was supported by National Heart, Lung, and
Blood Institute Research Grants HL-36597 and HL-40362.
Address for reprint requests and other correspondence:
S. J. Lai-Fook, Center for Biomedical Engineering, Wenner-Gren
Research Laboratory, Univ. of Kentucky, Lexington, KY 40506-
0070 (E-mail: laifook@uky.edu).
Downloaded from http://physrev.physiology.org/ by 112.215.200.134 on November 27, 2017
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